Predicting in vivo effect levels for repeat-dose systemic toxicity using chemical, biological, kinetic and study covariates

Archives of Toxicology
Lisa TruongMatthew T Martin

Abstract

In an effort to address a major challenge in chemical safety assessment, alternative approaches for characterizing systemic effect levels, a predictive model was developed. Systemic effect levels were curated from ToxRefDB, HESS-DB and COSMOS-DB from numerous study types totaling 4379 in vivo studies for 1247 chemicals. Observed systemic effects in mammalian models are a complex function of chemical dynamics, kinetics, and inter- and intra-individual variability. To address this complex problem, systemic effect levels were modeled at the study-level by leveraging study covariates (e.g., study type, strain, administration route) in addition to multiple descriptor sets, including chemical (ToxPrint, PaDEL, and Physchem), biological (ToxCast), and kinetic descriptors. Using random forest modeling with cross-validation and external validation procedures, study-level covariates alone accounted for approximately 15% of the variance reducing the root mean squared error (RMSE) from 0.96 log10 to 0.85 log10 mg/kg/day, providing a baseline performance metric (lower expectation of model performance). A consensus model developed using a combination of study-level covariates, chemical, biological, and kinetic descriptors explained a total o...Continue Reading

References

Apr 1, 1992·Regulatory Toxicology and Pharmacology : RTP·W Leisenring, L Ryan
Nov 25, 2003·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·R KroesUNKNOWN European branch of the International Life Sciences Institute
Sep 12, 2006·Toxicological Sciences : an Official Journal of the Society of Toxicology·David J DixRobert J Kavlock
Jun 24, 2008·Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews·Natalja FjodorovaEmilio Benfenati
Apr 2, 2009·Environmental Health Perspectives·Matthew T MartinDavid J Dix
Apr 28, 2009·Regulatory Toxicology and Pharmacology : RTP·Pauline McNameeJulia Scheel
Jun 17, 2009·Journal of Chemical Information and Modeling·Viviana ConsonniRoberto Todeschini
Mar 13, 2010·Archives of Toxicology·Bernd RuppUrsula Gundert-Remy
Apr 7, 2010·Environmental Health Perspectives·Richard S JudsonDavid J Dix
Jun 25, 2010·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Daniel KrewskiLauren Zeise
Jul 20, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Daniel M RotroffRussell S Thomas
Sep 10, 2010·Environmental Health Perspectives·David M ReifRobert J Kavlock
Feb 23, 2011·PloS One·Imran ShahDavid J Dix
Mar 23, 2011·Journal of Computational Chemistry·Chun Wei Yap
May 14, 2011·Biology of Reproduction·Matthew T MartinDavid J Dix
Aug 30, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Nisha S SipesThomas B Knudsen
Sep 29, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Barbara A WetmoreRussell S Thomas
Apr 4, 2013·SAR and QSAR in Environmental Research·Y SakurataniM Hayashi
Apr 25, 2013·Chemical Research in Toxicology·Nisha S SipesThomas B Knudsen
Jul 3, 2013·Toxicology in Vitro : an International Journal Published in Association with BIBRA·S PfuhlerJ Barroso
Feb 20, 2014·Basic & Clinical Pharmacology & Toxicology·Henrik Johansson, Malin Lindstedt
May 20, 2014·Nature Biotechnology·Nicole C KleinstreuerKeith A Houck
Nov 6, 2014·ALTEX·Tilman GochtMaurice Whelan
Dec 19, 2014·Environmental Science and Pollution Research International·Alla P ToropovaAleksandar M Veselinović
Apr 9, 2015·Molecular Diversity·Andrey A ToropovEmilio Benfenati
Apr 10, 2016·European Journal of Medicinal Chemistry·Jovana B VeselinovićAndrey A Toropov
Apr 28, 2016·Chemical Research in Toxicology·Sergii NovotarskyiIgor V Tetko
Sep 9, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Richard JudsonRussell S Thomas
Jul 17, 2017·Journal of Statistical Software·Robert G PearceNisha S Sipes

❮ Previous
Next ❯

Citations

Mar 6, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Russell S ThomasAntony J Williams
May 22, 2021·Computational Toxicology·Prachi PradeepRichard Judson
Sep 29, 2019·Environmental Science & Technology·Thomas Y Sheffield, Richard S Judson

❮ Previous
Next ❯

Software Mentioned

ToxRefDB
DB
PaDEL
ChemoTyper
R package
R
prcomp
ToxPrint
httk
COSMOS

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.